There are numerous methods known in the art to prepare nucleoside analogs, wherein such compounds may include modifications on the heterocyclic base as well as on the sugar moiety. In some approaches, modifications are introduced into the already synthesized nucleoside to yield the desired nucleoside analog, while in other approaches the sugar portion is modified and then coupled to the heterocyclic base (which may or may not be modified) to generate the desired nucleoside analog.
However, and particularly where the desired nucleoside analogs include reactive groups (e.g., OH groups in the sugar, NH2 group in the heterocyclic base), various difficulties are frequently encountered. For example, where the modification of the heterocyclic base and/or the sugar portion in a nucleoside requires relatively strong acidification or other relatively harsh conditions, the glycosidic bond in the nucleoside may be destroyed in the process. In another example, modification reagents may react not only with the desired functional group(s) in the heterocyclic base, sugar, and/or nucleoside, but may also modify reactive groups where those are unprotected. Moreover, even where relatively high selectivity may be achieved using protecting groups and modification reagents using particular reaction conditions, such conditions may lead to subsequent problems in isolation, isomeric purification, and/or instability of the desired product.
Thus, although there are numerous methods known in the art to produce nucleoside analogs, all or almost all of them suffer from one or more disadvantages. Therefore, there is still a need for improved methods and compositions for synthesized nucleoside analogs, and especially those with a 2′-beta-methyl modified sugar and an N6-modified adenine base.